Design, Synthesis and in vitro Evaluation of Primaquine and Diaminoquinazoline Hybrid Molecules Against the Malaria Parasite

In this study, we built on the known inhibitory potential of diaminoquinazolines (DAQs) against different stages of Plasmodium development and designed a convenient two-step synthesis to combine DAQ with primaquine (PQ) pharmacophore. The PQ-DAQ hybrids displayed potent in vitro activities in the low nanomolar range (IC₅₀ 135.20-398.80 nM) against all intra-erythrocytic stages of the drug-sensitive 3D7 strain, with significant potency enhancement compared to PQ alone (IC₅₀ 9370 nM). These hybrids were also potent at killing drug-resistant strains (Dd2, Dd2 R539T, IPC4912, CamWT C580Y, and 7G8) in the nanomolar range, with 11 f being the most effective compound (IC₅₀ 172.20-396.60 nM). Notably, for the first time, we present evidence that the DAQ-based compound 8 and its hybrids can inhibit β-hematin formation in vitro with potency (IC₅₀ 0.90-27.80 μM), suggesting hemozoin formation to be one of the potential targets of this series. Lastly, two hybrids with potent antiplasmodial activity were also found to be safe up to 10 μM against human HepG2 cells, suggesting the possibility of achieving host vs parasite selectivity with this series.